1. Technical Field
The invention relates to the use of a phosphodiesterase type III (PDE III) inhibitor or a “Ca2+-sensitizing agent” or a pharmaceutically acceptable derivative thereof for the preparation of a medication for the reduction of the heart size of a patient suffering from heart failure, and a medication for the reverse remodelling of the heart of a patient with asymptomatic (occult) heart failure and their delayed onset of clinical symptoms.
2. Background Information
Heart failure is divided in different stages (ISACHC-Stages-Class I-III). The pathology of the heart begins with ISACHC Class I in which cardiac murmur or cardiac chamber enlargement, but no clinical symptoms are present (Class I or occult stage). Heart insufficiency scoring is used herein, and the following is a description of the scoring so used.
Degree of heart insufficiency was evaluated using a 5-class score adapted from the International Small Animal Cardiac Health Council (ISACHC) System of Heart Failure Classification:
Class I: The Asymptomatic Patient (Heart Disease Associated with No Clinical Signs)                Heart disease is detectable (e.g. cardiac murmur, arrhythmia, or cardiac chamber enlargement that is detected by radiography or echocardiography); however the patient is not overtly affected and does not demonstrate clinical signs of heart failure. The need for treatment at this stage is arguable but not justifiable with currently available data.        The stage is subdivided as follows:        A.: Signs of heart disease are present but no signs of compensation (volume or pressure overload ventricular hypertrophy) are evident (Class IA).        B.: Signs of heart disease are present and signs of compensation (volume or pressure overload ventricular hypertrophy) are detected radiographically or echocardiographically (Class IB).        
Class II: Mild-to-Moderate Heart Failure                Clinical signs of heart failure are evident at rest or with mild exercise, and adversely affect the quality of life. Typical signs of heart failure include exercise intolerance, cough, tachypnoea, mild respiratory distress (dyspnoea), and mild to moderate ascites. Hypoperfusion at rest is generally not present (Class II). Home treatment is often indicated at this stage.        
Class III: Advanced Heart Failure                A.: Clinical signs of advanced congestive heart failure are immediately obvious. These clinical signs could include respiratory distress (dyspnoea), marked ascites, profound exercise intolerance, or hypoperfusion at rest. In the most severe cases, the patient is moribund and suffers from cardiogenic shock. Death or severe debilitation is likely without therapy.        B.: Patients with advanced heart failure are divided into two Subcategories:                    1. Home care is possible (Class IIIA).            2. Hospitalisation is mandatory (cardiogenic shock, life-threatening oedema, or a large pleural effusion is present) (Class IIIB).                        
It is known that the progress of heart failure is associated with an increase of the size of the heart. In dilated cardiomyopathy (DCM), the ratio of left ventricular wall thickness to chamber diameter is decreased and the circumferences of the annuluses of the mitral and tricuspid valves are increased in proportion to the magnitude of chamber dilation. DCM may either be caused primarily, e.g. by genetic abnormalities, or secondarily, e.g. due to valvular insufficiency, both resulting in cardiac volume overload. However, it involves usually cardiac remodeling that may be defined as genome expression, molecular, cellular, and interstitial changes manifested clinically as changes in size, shape, and function of the heart. Cardiac remodelling is generally an adverse sign and linked to heart failure progression. Reverse cardiac remodelling is a goal of the treatment of heart failure therapy.
Heart failure therapy has traditionally focused largely on symptomatic relief rather than on addressing underlying disease problems. Many dogs with symptomatic DCM have a very guarded prognosis (Monnet et al., 1995), with Dobermanns in particular generally experiencing only short survival times (Calvert et al., 1982; Calvert et al., 1997). There have been few studies examining the influence of treatment on survival in dogs with symptomatic DCM, although a subanalysis of the dogs with DCM in the LIVE study showed an improvement in time to treatment failure in those dogs receiving enalapril compared with placebo (142.8 versus 56.5 days, respectively) (Ettinger et al., 1998). On the whole, oral positive inotropic agents have lost favour in the treatment of chronic heart failure in human patients in recent years, after a number of trials revealed adverse effects on survival despite short-term hemodynamic benefits (Packer et al., 1991; Cowley and Skene, 1994). Recently it has been suggested that calcium sensitising agents may result in positive inotropic effects without producing some of the adverse effects (including calcium overload) associated with more traditional positive inotropes such as dobutamine, amrinone and milrinone.
In ISACHC Class I stage heart failure, in which cardiac murmur or cardiac chamber enlargement, but no clinical symptoms are present, therapy would have two objectives:                reduce the pathologic changes of the dimensions of the heart (to the normal parameters—“reverse remodelling”); and        prolong the time until onset of clinical symptoms.        
However, there is currently no drug available which has proven to be efficacious in the reduction of the pathologic changes of the dimensions of the heart to the normal parameters (“reverse remodelling”) at asymptomatic stage (ISACHC Class I). A study has been published with the use of ACE-Inhibitors in the asymptomatic stage, but no therapeutic effect was shown (SVEP Trial), neither a reverse remodelling nor a prolongation of the time until onset of clinical symptoms.
When the pathology progresses and clinical symptoms are also present (Class II or III), several drugs showed a benefit in quality of life and some also in survival time. These drugs include phosphodiesterase type III (PDE III) inhibitors or “Ca2+-sensitizing agents”, for example cilostazol, pimobendan, milrinone, levosimendan, amrinone, enoximone and piroximone TZC-5665, etc. Rather than increasing calcium entry into cardiac myocytes, calcium sensitisers achieve their positive inotropic effect by sensitising the contractile proteins to existing cytosolic calcium, by altering the binding of calcium with troponin-C. Producing a positive inotropic effect by calcium sensitising thereby avoids some of the adverse effects of cytosolic calcium overload. Increased cytosolic calcium levels have been associated with an increased tendency for arrhythmias and sudden death. Clinical trials of long-term use of oral pimobendan in human patients with heart failure have demonstrated an improvement in exercise tolerance and quality of life without significantly adverse effects on survival (Kubo et al., 1992; Katz et al., 1992).
The problem underlying the present invention was to provide a medication, which increases the time without clinical symptoms and remodels the size of the heart to reduce the risk of death in patients with asymptomatic heart disease (ISACHC Class I).